We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Four individually druggable MET hotspots mediate HGF-driven tumor progression.
- Authors
Basilico, Cristina; Hultberg, Anna; Blanchetot, Christophe; de Jonge, Natalie; Festjens, Els; Hanssens, Valerie; Osepa, Sjudry-Ilona; De Boeck, Gitte; Mira, Alessia; Cazzanti, Manuela; Morello, Virginia; Dreier, Torsten; Saunders, Michael; de Haard, Hans; Michieli, Paolo
- Abstract
Activation of MET by HGF plays a key role in tumor progression. Using a recently developed llama platform that generates human-like immunoglobulins, we selected 68 different antibodies that compete with HGF for binding to MET. HGF-competing antibodies recognized 4 distinct hotspots localized in different MET domains. We identified 1 hotspot that coincides with the known HGF β chain binding site on blades 2-3 of the SEMA domain β-propeller. We determined that a second and a third hotspot lie within blade 5 of the SEMA domain and IPT domains 2-3, both of which are thought to bind to HGF α chain. Characterization of the fourth hotspot revealed a region across the PSI-IPT 1 domains not previously associated with HGF binding. Individual or combined targeting of these hotspots effectively interrupted HGF/MET signaling in multiple cell-based biochemical and biological assays. Selected antibodies directed against SEMA blades 2-3 and the PSI-IPT 1 region inhibited brain invasion and prolonged survival in a glioblastoma multiforme model, prevented metastatic disease following neoadjuvant therapy in a triple-negative mammary carcinoma model, and suppressed cancer cell dissemination to the liver in a KRAS-mutant metastatic colorectal cancer model. These results identify multiple regions of MET responsible for HGF-mediated tumor progression, unraveling the complexity of HGF-MET interaction, and provide selective molecular tools for targeting MET activity in cancer.
- Subjects
HEMATOPOIETIC growth factors; MET gene; CANCER invasiveness; IMMUNOGLOBULINS; COLON cancer
- Publication
Journal of Clinical Investigation, 2014, Vol 124, Issue 7, p3172
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI72316